CHK1 dosage in germinal center B cells controls humoral immunity

Schoeler, Katia; Jakic, Bojana; Heppke, Julia; Soratroi, Claudia; Aufschnaiter, Andreas; Hermann-Kleiter, Natascha; Villunger, Andreas; Labi, Verena

doi:10.1038/s41418-019-0318-5

Cited by 16 publications

(25 citation statements)

References 60 publications

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“…[62] using the following fluorochrome-labelled antibodies: aB220-PerCP/Cy5.5 (BioLegend, 103236, 1 : 300), aB220-BV510 (BioLegend, 103247, 1 : 300), aCD19-BV605 [62] using the following fluorochrome-labelled antibodies: aB220-PerCP/Cy5.5 (BioLegend, 103236, 1 : 300), aB220-BV510 (BioLegend, 103247, 1 : 300), aCD19-BV605 …”

Section: Flow Cytometry Analysis Of Ex Vivo Isolated Cellsmentioning

confidence: 99%

“…The following primers were used: HPRT F: ELISA For NP-specific serum IgG1 and IgM titres, ELISA was performed as described in [62]. RNA from snap-frozen in vitro-cultivated B cells was isolated using Trizol reagent (Thermo Fisher Scientific, 15596026) as per manufacturer's instructions.…”

Section: Quantitative Real-time-pcrmentioning

confidence: 99%

“…Flow cytometry analysis has been performed as described in Ref. [62] using the following fluorochrome-labelled antibodies: aB220-PerCP/Cy5.5 (BioLegend, 103236, 1 : 300), aB220-BV510 (BioLegend, 103247, 1 : 300), aCD19-BV605…”

Section: Flow Cytometry Analysis Of Ex Vivo Isolated Cellsmentioning

confidence: 99%

“…Cell sorting has been performed as described in Ref. [62]. Briefly, bone marrow or splenic single-cell suspensions were pre-incubated with 1 lgÁmL À1 of aCD16/32 Fc-Block in 500 lL staining buffer (PBS/3%FBS) for 10 min, washed and stained for 20 min with antibodies in a volume of 500 lL staining buffer.…”

Section: Cell Sortingmentioning

confidence: 99%

“…The expression of individual mRNAs was normalized to HPRT with the following formula: fold induction = 2 ðÀDCtÞ , where DC t ¼ C t ðtargetÞ À C t ðHPRTÞ . The following primers were used: HPRT F: 5 0 -GTCATGCCGACCCGC AGTC-3 0 , HPRT R: ELISA For NP-specific serum IgG1 and IgM titres, ELISA was performed as described in [62]. For total immunoglobulin levels in serum or secreted immunoglobulin in iGC culture medium, 50 lgÁmL À1 capture antibody (Southern Biotech, 1010-01) was coated overnight onto 96-well enzyme-linked immunosorbent assay plates at 4°C (Sigma, CLS3590).…”

Section: Quantitative Real-time-pcrmentioning

confidence: 99%

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TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells

et al. 2019

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Upon activation by antigen, B cells form germinal centres where they clonally expand and introduce affinity‐enhancing mutations into their B‐cell receptor genes. Somatic mutagenesis and class switch recombination (CSR) in germinal centre B cells are initiated by the activation‐induced cytidine deaminase (AID). Upon germinal centre exit, B cells differentiate into antibody‐secreting plasma cells. Germinal centre maintenance and terminal fate choice require transcriptional reprogramming that associates with a substantial reconfiguration of DNA methylation patterns. Here we examine the role of ten‐eleven‐translocation (TET) proteins, enzymes that facilitate DNA demethylation and promote a permissive chromatin state by oxidizing 5‐methylcytosine, in antibody‐mediated immunity. Using a conditional gene ablation strategy, we show that TET2 and TET3 guide the transition of germinal centre B cells to antibody‐secreting plasma cells. Optimal AID expression requires TET function, and TET2 and TET3 double‐deficient germinal centre B cells show defects in CSR. However, TET2/TET3 double‐deficiency does not prevent the generation and selection of high‐affinity germinal centre B cells. Rather, combined TET2 and TET3 loss‐of‐function in germinal centre B cells favours C‐to‐T and G‐to‐A transition mutagenesis, a finding that may be of significance for understanding the aetiology of B‐cell lymphomas evolving in conditions of reduced TET function.

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Section: Flow Cytometry Analysis Of Ex Vivo Isolated Cellsmentioning

confidence: 99%

Section: Quantitative Real-time-pcrmentioning

confidence: 99%

Section: Flow Cytometry Analysis Of Ex Vivo Isolated Cellsmentioning

confidence: 99%

Section: Cell Sortingmentioning

confidence: 99%

Section: Quantitative Real-time-pcrmentioning

confidence: 99%

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TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells

et al. 2019

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ATR-CHK1 pathway as a therapeutic target for acute and chronic leukemias

Boudný

Trbušek

2020

Cancer Treatment Reviews

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Targeting the DNA damage response for patients with lymphoma: Preclinical and clinical evidences

Carrassa¹,

Colombo

Damia

et al. 2020

Cancer Treatment Reviews

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The DNA damage response (DDR) is a well-coordinated cellular network activated by DNA damage. The unravelling of the key players in DDR, their specific inactivation in different tumor types and the synthesis of specific chemical inhibitors of DDR represent a new hot topic in cancer therapy. In this article, we will review the importance of DDR in lymphoma development and how this can be exploited therapeutically. Specifically, we will focus on CHK1, WEE1, ATR, DNA-PK and PARP inhibitors, for which preclinical data as single agents or in combination has been accumulating, fostering their clinical development. The few available clinical data on these inhibitors will also be discussed.

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CHK1 dosage in germinal center B cells controls humoral immunity

Cited by 16 publications

References 60 publications

TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells

TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells

ATR-CHK1 pathway as a therapeutic target for acute and chronic leukemias

Targeting the DNA damage response for patients with lymphoma: Preclinical and clinical evidences

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